Zebrafish as an Experimental and Preclinical Model for Alzheimer’s Disease

Abstract

The success rate of novel drug candidates in clinical trials relies on the safety and efficacy data of the preclinical studies. Although cell-based assays are widely used, the complexity of an in vivo system to mimic human disease pathophysiology is essential. Despite the wide usage of rodent models for preclinical drug discovery, increasing the repertoire of animal models that allow the investigation of various pathological mechanisms with a unique operational strength for drug discovery is required. Zebrafish, a teleost vertebrate, with its high similarity to human pathophysiology and unique tissue regenerative ability, emerged as an excellent tool for early drug discovery and preclinical studies.

ABCA7-dependent Neuropeptide-Y signalling is a resilience mechanism required for synaptic integrity in Alzheimer’s disease

“…While brains in zebrafish and humans are evolutionarily distinct, pathological mechanisms of AD may be parallel 6,7,14,15,[17][18][19][20][21]26,28,29,51 , exemplified by the remarkable similarity of molecular changes in neurons after amyloid toxicity 51 . Thus, we hypothesized that NPY and BDNF signaling might be altered in AD patients.…”

“…We developed a zebrafish model of amyloid toxicity, which shows strong parallels in the cellular and molecular mechanisms of the disease, including vascular perturbations, neurodegeneration, and immune reaction 6-13 . This model has enabled functional investigation of AD genetic variants 14-16 and development of new active and potent pharmacological agents 6,17, 18 . One of the key strengths of zebrafish is its remarkable neuro-regenerative ability after amyloid toxicity, which involves activation of molecular mechanisms that govern astroglial proliferation 19-24 .…”

“…Organisms that share conserved genetic elements with humans, offer a valuable platform for robust functional analysis. We developed a zebrafish model of amyloid toxicity, which shows strong parallels in the cellular and molecular mechanisms of the disease, including vascular perturbations, neurodegeneration, and immune reaction [6][7][8][9][10][11][12][13] . This model has enabled functional investigation of AD genetic variants [14][15][16] and development of new active and potent pharmacological agents 6,17,18 .…”

The Evaluation of Neuroprotective Effect of Nigella sativa Linn Seed Using Zebrafish Model

“…The zebrafish (Danio rerio) is a unique model animal for biomedical research, including studies of biological processes and human diseases. Zebrafish are sometimes identified as relative to classic rodent models or alternative models, but the use of fish in addition to classic mammalian models [6]. The role of frontal cortical and hippocampal structures in learning and memory cannot be studied with fish since these are not evident, but other attributes of fish make them valuable models in behavioral neuroscience research.…”

Ngfr suppresses Lcn2/Slc22a17 signaling, induces neurogenesis and reduces amyloid pathology in the hippocampus of APP/PS1dE9 mouse

“…We previously generated an adult AD zebrafish model and found that a complex set of cellular crosstalk leads to production of more neurons despite the disease ongoing pathology [9][10][11][12] . This model has strong parallelism to human AD brains in terms of molecular programs affected by AD pathology 13 , served as a pre-clinical tool for drug screening [14][15][16] and helped identify genes associated with AD in humans 17,18 . The extraordinary regenerative ability of astroglia in zebrafish in AD-like scenarios rely on set of molecular mechanisms, one of which is the pro-neurogenic activity through the expression of nerve growth factor receptor (ngfra) 9, 19 .…”